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UMMC Guidance for Multisystem Inflammatory Syndrome in Children (MIS-C) Version 3

Note:  Note:  Guidance is based on expert consensus. Subspecialty consultation for individualized recommendations for suspected cases is strongly recommended. The Version 3 Guidlelines also highlight that “…at this time, given the high prevalence of COVID-19 in certain communities, seropositvity to SARS-CoV-2 (nucleocapsid or spike protein) may no longer adequately distinguish between MIS-C and other overlapping syndromes, although a negative antibody test should prompt consideration of alternative diagnoses…”.

Case Definition for Multisystem Inflammatory Syndrome in Children (MIS-C)*

  • A patient aged <21 years presenting with fever, laboratory evidence of inflammation, and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological); AND
  • No alternative plausible diagnoses; AND
  • Positive for recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or COVID-19 exposure within 4 weeks prior to the onset of symptoms
  • Fever >38.0°C for ≥24 hours, or report of subjective fever lasting ≥24 hours
  • Evidence of inflammation: an elevated CRP, ESR, fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase (LDH), or interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes and low albumin
  • Reporting of these cases is completed via Infection Prevention (not necessary for providers to do this themselves)
  • Consider MIS-C in any pediatric death with evidence of SARS-CoV-2 infection

* (


*Figure 1 below used with Copyright License.

Clinical Guidance for Pediatric Patients with Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with SARS-CoV-2 and Hyperinflammation in COVID-19 - PDF


  • All children admitted with concern for MIS-C: Peds ID, Peds Cardiology*, Peds Rheumatology, Peds Hematology
  • If with concern for thrombosis/HLH/MAS: Peds Heme/Onc and Peds Rheumatology
  • If with severe abdominal pain: Peds GI, Peds Surgery
  • If with neurologic findings: Peds Neurology
  • Additional consults based on presenting symptoms and clinical indications (Peds Nephrology, Peds Neurology, Dermatology)
*Please note Pediatric Cardiology UMMC Guidelines for MISC posted also at this website:


Therapeutic Categories:

  • Steroid Initial Dosing – the use of steroid should be discussed with Peds Rheumatology
  • Immunomodulators – the use of anakinra or other biologics for refractory illness course should be discussed with Peds Rheumatology and Peds Heme Onc
  • Anticoagulation – the use of LMWH or other anticoagulation regimen should be discussed with Peds Heme Onc
  • GI prophylaxis with PPI – while on steroid c/o primary team
  • Steroid taper – with subspecialty consultation Peds Rheumatology


  • All children meeting MIS-C criteria or with coronary ectasia should receive IVIG 2g/kg SLOW INFUSION and strongly consider dividing into two doses after subspecialty discussion (not to EXCEED 80 gm/dose/infusion).
  • If 2-19 years of age should dose per IBW if actual body weight is > IBW by 20%. (and adults with BMI >30kg/m2)
  • Steroids should be considered also and discussed with PEDS Rheum and PEDS ID


  • Antibiotics: Ceftriaxone (alternative, ceftazidime) should be used as first-line empiric antibiotic coverage.
    • Add vancomycin if concerned for MRSA infection, including skin or soft tissue source, pneumonia, Gram positive bacteremia
    • Add metronidazole if concerned for intra-abdominal infection.
    • Use cefepime (alternative, meropenem) for patients who are immunocompromised, have a history of multi-drug resistant gram-negative bacterial infections, are critically ill, or if otherwise clinically indicated.
    • Consider further coverage for toxic shock syndrome or Rickettsia infection depending on patient presentation.
  • Anticoagulation: Please consult Heme/Onc to discuss. Please consider contraindications to anticoagulation (i.e., patients w/ PLT <30,000-80,000/uL, active bleeding, or significant bleeding risk). In general low dose ASA 3-5 mg/kg/day should be given until normalization of platelet count and confirmed normal coronaries at >/= 4 weeks after diagnosis. Enoxaparin should be considered also as prophylaxis/treatment (treatment dosing considered with coronary artery aneurysms with z score >/=10 or patients with documented thrombosis or an ejection fraction <35%).
  • Patients with GI Symptoms: These patients have higher risk of bowel perforation with pulse steroids. Consider risk/benefit of therapy in these patients. Please consult rheumatology for recommendations for steroids.
  • Patients with Renal Injury: Consult Peds Nephrology and pediatric pharmacy for assistance in dosing medications


Dermatologic: Take photo of rash/upload to Epic, Consider the following tests (HSV, VZV, enterovirus PCR); Consider alternative rheumatologic diagnoses that present with fever and rash – Systemic JIA, Lupus, Kawasaki disease. GI: Consider GI pathogen PCR panel; C difficile toxin PCR; Stool culture; Neurologic: Head imaging – consider if with focal neurologic deficit, altered mental status, seizure, severe headache with meningeal signs. If no contraindications, perform lumbar puncture (cell count, protein, glucose, culture, meningoencephalitis panel) AND CONSULT NEUROLOGY.


PICUGeneral Pediatric Floor
  • Cardiac enzymes & BNP – every 48 hours (trend daily if abnormal)
  • 12L ECG every 1-2 days
  • ECHO – timing– discuss with Peds Cardiology
  • Cardiac enzymes & BNP – weekly (trend daily if abnormal)
  • 12L ECG every 2 days
  • ECHO –discuss with Peds Cardiology
  • Discuss with Peds Rheumatology regarding daily labs (CBC diff, CMP, ferritin, fibrinogen, D-dimer, triglycerides) for patients concerning for cytokine storm
  • Clinical change or abnormal trends/other labs warrant further evaluation to be determined by primary team


  • Steroid taper plan should be determined and clarified with Pediatric Rheumatology-please confirm that patient has prescription picked up and that patient is provided with prescription and medication/dispense quantity prior to discharge. The prescription wean can be written as directions but please ensure steroids dispensed are sufficient for the wean period. Please call Rheum to clarify if there is any need.
  • Ensure that plan for discharge ASA and enoxaparin are clear with Cardiology and Hematology and the parent. (e.g., if patient needs ASA if it is not given as an RX (tell the parents they have to get it separately).
  • Consider GI protective agent as many patients will be going home on ASA and steroid weans
  • All patients should have follow-up within 2 weeks post discharge with Pediatric Cardiology with repeat ECHO, ECG, and MIS-C clinic for PEDS ID, RHEUM, and HEME follow up. Prior to discharge, Pediatric Hematology should be contacted to discuss discharge plans for anticoagulation (e mail/contact Dr Cathy Gordon if there are needs for clarification). 
  • FOR APPOINTMENTS, PRIOR TO DISCHARGE, please e-mail JEANIE CRAFT at  Make sure REF300 is entered for Cardiology and CHAMB CHS MIS-C CLINIC (request 3 visits). 
  • Exercise should be LIMITED until outpatient Cardiology appointment clears the child for resumption of activity
  • Live vaccines are not to be administered within 11 months of IVIG due to decreased potential efficacy.
  • Consider influenza shot (killed vaccine) if due, but ideally at least 1 month after cessation of steroids.
  • CDC recommends deferring COVID-19 vaccination for eligible children to 3 months post-MISC and clinical recovery has been achieved, including return to normal cardiac function; and onset of MIS-C occurred before any COVID-19 vaccination.
  • Return to physical activity should be limited as per and assessment/clearance by Pediatric Cardiology.

Contributors: Robert Santos, MD, April Palmer, MD, Charlotte Hobbs, MD (Pediatric Infectious Disease); Anita Dhanrajani, MD, (Pediatric Rheumatology); Catherine Gordon, MD (Pediatric Hematology/Oncology); Divya Shakti, MD and Bill Moskowitz, MD  (Pediatric Cardiology); Claire Gilliam, MD (Pediatric Hospitalist); Jenny Hong (PICU), Jeanie Craft (Pediatric Infectious Disease, MIS-C Clinic Coordinator).


Suggested readings and additional online resources for specialists caring for children with MIS-C:

American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS–CoV‐2 and Hyperinflammation in Pediatric COVID‐19: Version 3.
Available at

The Children’s Hospital of Philadelphia (CHOP) clinical pathway for evaluation of possible MIS-C, Kawasaki pathway, suspected MIS-C with shock, and sepsis pathway:

Centers for Disease Control and Prevention. Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19).
Available at:

American Academy of Pediatrics, COVID-19 Interim Guidance: Return to Sports and Physical Activity.
Available at:

Centers for Disease Control and Prevention. Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Approved or Authorized in the United States.
Available at: